Atrial fibrillation (AF) is the most common of all cardiac arrhythmias, afflicting nearly 5.5 million people worldwide. The Cox-Maze (CM) procedure is currently the surgical gold standard for the treatment of AF, and the number of operations performed annually has increased greatly in the last six to seven years. Radiofrequency (RF) ablation has made the operation safer and faster to perform, and new guidelines have named surgery as a complimentary modality to catheter based approaches to AF. However, only a paucity of information exists on the physiologic effects of the CM procedure. Moreover, it is thought that enlargement in atrial size and extensive fibrosis from structural remodeling increase the failure rate of this operation, but there is currently no method capable of predicting outcomes in individual patients. The first part of this proposal aims to precisely describe the effects that persistent AF has on atrial hemodynamics and structural remodeling. A Hanford mini-swine model of persistent AF will be employed whereby the animals will be atrially paced at 400 bpm with the ventricular response rate maintained at 3:1 to 5:1. These animals will undergo a cardiac MRI (cMRI) scan prior to initiation of rapid pacing and again after two months in simulated AF. Data from both time points will be correlated with pressure-volume data from conductance catheters and compared to controls. At the terminal study, all four chambers of the heart and both atrial appendages will be sampled and undergo histological analysis to evaluate the degree of nuclear changes, fibrosis, glycogen accumulation, myolysis and apoptosis. Immunohistochemistry and Western blotting will also be used to localize and quantitate pro- and anti-apoptotic proteins. Additionally, all animals will undergo a delayed-enhancement (DE)-MRI scan at baseline and after two months, and atrial enhancement will be correlated with histology in an attempt to validate DE-MRI as a method able to detect the degree of atrial fibrosis. The second part of this proposal will test the effect of each of the individual CM IV lesion sets on atrial function in the same swine model of persistent AF. The animals will be randomized to six groups and undergo a modified CM procedure. Animals will undergo pulmonary vein isolation, as well as the right and left atrial (LA) lesions that comprise the CM IV procedure in a different sequence in each of the six groups. Pressure-volume data will be taken before and after each lesion set. The first reading will give us baseline function after two months of persistent AF and the final reading will give us function after the full CM IV lesion set has been completed, thereby allowing us to quantify the effects of each lesion in relation to both the entire operation and hemodynamic changes from AF itself. Finally, we plan to test the effect that removal or ablation of the left atrial appendage (LAA) has on LA function. The LAA will undergo bipolar RF ablation at the base and either be allowed to remain electrically silent or paced synchronously with the rest of the LA in ten mini-swine. Function will be recorded using conductance catheters at baseline, in the above two scenarios and following clamping. PUBLIC HEALTH RELEVANCE: This proposal will determine the effects of persistent atrial fibrillation on cardiac function, correlate the hemodynamic changes with structural remodeling, and attempt to validate a novel MRI method that is used to assess atrial fibrosis and has the potential to aid a surgeon in predicting which individual patients will or will not respond to the Cox-Maze procedure. Moreover, the effects of the separate lesion sets that comprise the Cox- Maze IV operation will be examined sequentially in order to learn what detriment the operation has on cardiac function in the setting of persistent atrial fibrillation. The knowledge gained from this study will inform the expanded use of the Cox-Maze procedure that is seen in current clinical practice, direct future surgical approaches to the arrhythmia and elucidate the pathophysiology in an important animal model of atrial fibrillation.